AIM To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells(h UC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis.METHODS A CCl4-induced li...AIM To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells(h UC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis.METHODS A CCl4-induced liver fibrotic/cirrhotic rat model was used to assess the effect of h UC-MSCs. Histopathology was assessed by hematoxylin and eosin(H&E), Masson trichrome and Sirius red staining. The liver biochemical profile was measured using a Beckman Coulter analyzer. Expression analysis was performed using immunofluorescent staining, immunohistochemistry, Western blot, and real-time PCR.RESULTS We demonstrated that the infused h UC-MSCs could differentiate into hepatocytes in vivo. Functionally, the transplantation of h UC-MSCs to CCl4-treated rats improved liver transaminases and synthetic function, reduced liver histopathology and reversed hepatobiliary fibrosis. The reversal of hepatobiliary fibrosis was likely due to the reduced activation state of hepatic stellate cells, decreased collagen deposition, and enhanced extracellular matrix remodeling via the up-regulation of MMP-13 and down-regulation of TIMP-1. CONCLUSION Transplanted h UC-MSCs could differentiate into functional hepatocytes that improved both the biochemical and histopathologic changes in a CCl4-induced rat liver fibrosis model. h UC-MSCs may offer therapeutic opportunities for treating hepatobiliary diseases, including cirrhosis.展开更多
AIM To evaluate the effects of phosphatase and tension homologue deleted on chromosome ten(PTEN) gene on collagen metabolism in hepatic fibrosis and the underlying mechanisms.METHODS rat primary hepatic stellate cells...AIM To evaluate the effects of phosphatase and tension homologue deleted on chromosome ten(PTEN) gene on collagen metabolism in hepatic fibrosis and the underlying mechanisms.METHODS rat primary hepatic stellate cells(HSCs) and human LX-2 cells were transfected with adenovirus containing c DNA constructs encoding wild-type PTEN(Ad-PTEN), PTEN mutant G129 E gene(Ad-G129E), and r NA interference constructs targeting the PTEN sequence PTEN short hairpin r NA to up-regulate and downregulate the expression of PTEN. HSCs were assayed using fluorescent microscopy, real-time polymerase chain reaction, and western blotting. Moreover, a CCl_4-induced rat hepatic fibrosis model was established to investigate the in vivo effects. Hematoxylin and eosin, and Masson's trichrome were used to assess the histological changes. The expression of collagen Ⅰ and Ⅲ was assessed using immunohistochemistry and western blot analysis.RESULTS Elevated expression of PTEN gene reduced serum levels of alanine transaminase and aspartate transaminase, decreased collagen deposition in the liver, and reduced hepatocyte necrosis. In contrast, knockdown of PTEN expression had an opposite effect, such as increased collagen deposition in the liver, and was molecularly characterized by the increased expression of matrix metalloproteinase(MMP)-13(P < 0.01) and MMP-2(P < 0.01), as well as decreased expression of the tissue inhibitor of metalloproteinase(TIMP)-1(P < 0.01) and TIMP-2(P < 0.01).CONCLUSION These data indicated that gene therapy using recombinant adenovirus encoding PTEN might be a novel way of treating hepatic fibrosis.展开更多
We analyzed three gene microarray datasets by GEO2R and obtained differential genes associated with ferroptosis in esophageal adenocarcinoma by obtaining the FerrDb database to obtain ferroptosis-related genes for the...We analyzed three gene microarray datasets by GEO2R and obtained differential genes associated with ferroptosis in esophageal adenocarcinoma by obtaining the FerrDb database to obtain ferroptosis-related genes for the intersection.To further elaborate on the functions of differentially expressed genes(DGEs),this study performed gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis on DEGs.We used the Kaplan-Meier plotter database to verify the effect of DGEs genes on the overall survival of esophageal adenocarcinoma.We performed univariate/multifactorial COX regression analysis of DGEs genes associated with esophageal adenocarcinoma prognosis by R language to obtain ferroptosis-associated independent prognostic genes.To further understand the relationship between the upstream molecules of independent prognostic genes and ferroptosis,we obtained the upstream regulatory molecules miRNAs and LncRNAs of prognosis-related ferroptosis genes with the help of the miRWalk database,Oncomi database and StarBase database.we obtained a total of 75 DEGs.These DGEs were mainly enriched in the cellular response to lipids,and negative regulation of intracellular.These DGEs were mainly enriched in the negative regulation of intracellular signaling,positive regulation of cell death,cellular autophagy,HIF-1 signaling pathway,microRNAs in cancer,and ferroptosis.We performed prognostic analysis and univariate/multifactorial COX regression analysis on 75 ferroptosis-related genes and established four independent genes for esophageal adenocarcinoma,ATF3,ATM,ATG5,and HMGB1.The study also established hsa-miR-876-5p,hsa-miR-186-5p,hsa-miR-421,hsa-miR-505-3p,hsa-miR-503-5p,hsa-miR-299-3p and hsa-miR-191-5p,seven miRNAs with upstream regulation of LncRNAs.these miRNAs can be competitively bound by LncRNAs to prevent the inhibition of translation of target gene expression by miRNAs.In conclusion,our study identified four esophageal adenocarcinoma independent prognostic genes and their upstream regulatory molecules.These genes are involved in the ferroptosis regulation of cells and also play an important role in tumor therapy and drug resistance as one of the disease therapeutic targets.The study suggests that by targeting ATF3,ATM,ATG5,HMGB1 and their upstream regulatory molecules is a new direction for the treatment of esophageal adenocarcinoma.展开更多
BACKGROUND Recent studies have emphasized the emerging importance of long noncoding RNAs(lncRNAs)in colorectal cancer(CRC).However,the functions and regulatory mechanisms of numerous lncRNAs in CRC have not been fully...BACKGROUND Recent studies have emphasized the emerging importance of long noncoding RNAs(lncRNAs)in colorectal cancer(CRC).However,the functions and regulatory mechanisms of numerous lncRNAs in CRC have not been fully elucidated.AIM To explore the functional role and underlying molecular mechanisms of lncRNA TNFRSF10A-AS1 in CRC.METHODS TNFRSF10A-AS1 expression was measured by quantitative real-time polymerase chain reaction in CRC,and the relationship between TNFRSF10A-AS1 levels and the clinicopathological features of CRC patients was analyzed.The effect of TNFRSF10A-AS1 expression on CRC proliferation and metastasis was examined in vitro and in vivo.Mechanistically,we investigated how TNFRSF10A-AS1 is involved in CRC as a competitive endogenous RNA.RESULTS TNFRSF10A-AS1 was expressed at a high level in CRC and the upregulation of TNFRSF10A-AS1 was associated with advanced T grade and tumor size in CRC patients.A functional investigation revealed that TNFRSF10A-AS1 enhanced the proliferation,migration ability and invasion ability of colon cancer cells in vitro and in vivo.A mechanistic analysis demonstrated that TNFRSF10A-AS1 acted as a miR-3121-3p molecular sponge to regulate HuR expression,ultimately promoting colorectal tumorigenesis and progression.CONCLUSION TNFRSF10A-AS1 exerts a tumor-promoting function through the miR-3121-3p/HuR axis in CRC,indicating that it may be a novel target for CRC therapy.展开更多
We analysed four gene microarray datasets by GEO2R and obtained differential genes expressed in oesophageal cancer.To further elaborate the functions of DGEs,this study performed gene ontology(GO)and Kyoto Encyclopedi...We analysed four gene microarray datasets by GEO2R and obtained differential genes expressed in oesophageal cancer.To further elaborate the functions of DGEs,this study performed gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of DEGs.We constructed protein interaction networks of DGEs through the String database and screened core genes.We used the GEPIA online database with the Kaplan-Meier plotter database to verify the expression of Hub genes in expressed normal versus tumour tissues and the effect of Hub genes on overall and disease-free survival in oesophageal cancer.To further understand the relationship between Hub gene and tumour metastasis,we analysed the difference in Hub gene expression in patients without metastatic oesophageal cancer versus those with metastatic oesophageal cancer with the help of the HCMDB database.The relationship between Hub genes and tumour immune infiltration was analysed by the TIMER database.We obtained a total of 149 DEGs,of which 49 were up-regulated genes and 100 were down-regulated genes.These DGEs were importantly enriched in IL-17 signalling pathway,ECM-receptor interactions,p53 signalling pathway,estrogen signalling pathway,complement and coagulation cascade response.We screened 10 Hub genes,MMP9,CXCL8,COL1A1,TIMP1,POSTN,MMP3,MMP1,COL3A1,SERPINE1,LUM,among 149 DGEs.hub genes were all up-regulated in expression in esophageal cancer tissues,in addition,MMP9,T1MP1,CXCL8,POSTN and The expression of COL3A1,LUM,MMP1,MMP3,MMP9,POSTN,SERPINE1 and TIMP1 was positively correlated with the infiltration of immune cells in the tumor microenvironment.In conclusion,our study identified 10 signature genes for oesophageal cancer.These genes are associated with the development,metastasis,prognosis and immune infiltration of oesophageal cancer and may be markers of development,metastasis and prognosis as well as targets for immunotherapy.展开更多
文摘AIM To investigate the hepatic differentiation potential of human umbilical cord-derived mesenchymal stem cells(h UC-MSCs) and to evaluate their therapeutic effect on liver fibrosis/cirrhosis.METHODS A CCl4-induced liver fibrotic/cirrhotic rat model was used to assess the effect of h UC-MSCs. Histopathology was assessed by hematoxylin and eosin(H&E), Masson trichrome and Sirius red staining. The liver biochemical profile was measured using a Beckman Coulter analyzer. Expression analysis was performed using immunofluorescent staining, immunohistochemistry, Western blot, and real-time PCR.RESULTS We demonstrated that the infused h UC-MSCs could differentiate into hepatocytes in vivo. Functionally, the transplantation of h UC-MSCs to CCl4-treated rats improved liver transaminases and synthetic function, reduced liver histopathology and reversed hepatobiliary fibrosis. The reversal of hepatobiliary fibrosis was likely due to the reduced activation state of hepatic stellate cells, decreased collagen deposition, and enhanced extracellular matrix remodeling via the up-regulation of MMP-13 and down-regulation of TIMP-1. CONCLUSION Transplanted h UC-MSCs could differentiate into functional hepatocytes that improved both the biochemical and histopathologic changes in a CCl4-induced rat liver fibrosis model. h UC-MSCs may offer therapeutic opportunities for treating hepatobiliary diseases, including cirrhosis.
基金Supported by the National Natural Science Foundation of China,No.30872513
文摘AIM To evaluate the effects of phosphatase and tension homologue deleted on chromosome ten(PTEN) gene on collagen metabolism in hepatic fibrosis and the underlying mechanisms.METHODS rat primary hepatic stellate cells(HSCs) and human LX-2 cells were transfected with adenovirus containing c DNA constructs encoding wild-type PTEN(Ad-PTEN), PTEN mutant G129 E gene(Ad-G129E), and r NA interference constructs targeting the PTEN sequence PTEN short hairpin r NA to up-regulate and downregulate the expression of PTEN. HSCs were assayed using fluorescent microscopy, real-time polymerase chain reaction, and western blotting. Moreover, a CCl_4-induced rat hepatic fibrosis model was established to investigate the in vivo effects. Hematoxylin and eosin, and Masson's trichrome were used to assess the histological changes. The expression of collagen Ⅰ and Ⅲ was assessed using immunohistochemistry and western blot analysis.RESULTS Elevated expression of PTEN gene reduced serum levels of alanine transaminase and aspartate transaminase, decreased collagen deposition in the liver, and reduced hepatocyte necrosis. In contrast, knockdown of PTEN expression had an opposite effect, such as increased collagen deposition in the liver, and was molecularly characterized by the increased expression of matrix metalloproteinase(MMP)-13(P < 0.01) and MMP-2(P < 0.01), as well as decreased expression of the tissue inhibitor of metalloproteinase(TIMP)-1(P < 0.01) and TIMP-2(P < 0.01).CONCLUSION These data indicated that gene therapy using recombinant adenovirus encoding PTEN might be a novel way of treating hepatic fibrosis.
基金supported by the fund project of Science and Technology Department of Qinghai Province(2021-ZJ-730).
文摘We analyzed three gene microarray datasets by GEO2R and obtained differential genes associated with ferroptosis in esophageal adenocarcinoma by obtaining the FerrDb database to obtain ferroptosis-related genes for the intersection.To further elaborate on the functions of differentially expressed genes(DGEs),this study performed gene ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis on DEGs.We used the Kaplan-Meier plotter database to verify the effect of DGEs genes on the overall survival of esophageal adenocarcinoma.We performed univariate/multifactorial COX regression analysis of DGEs genes associated with esophageal adenocarcinoma prognosis by R language to obtain ferroptosis-associated independent prognostic genes.To further understand the relationship between the upstream molecules of independent prognostic genes and ferroptosis,we obtained the upstream regulatory molecules miRNAs and LncRNAs of prognosis-related ferroptosis genes with the help of the miRWalk database,Oncomi database and StarBase database.we obtained a total of 75 DEGs.These DGEs were mainly enriched in the cellular response to lipids,and negative regulation of intracellular.These DGEs were mainly enriched in the negative regulation of intracellular signaling,positive regulation of cell death,cellular autophagy,HIF-1 signaling pathway,microRNAs in cancer,and ferroptosis.We performed prognostic analysis and univariate/multifactorial COX regression analysis on 75 ferroptosis-related genes and established four independent genes for esophageal adenocarcinoma,ATF3,ATM,ATG5,and HMGB1.The study also established hsa-miR-876-5p,hsa-miR-186-5p,hsa-miR-421,hsa-miR-505-3p,hsa-miR-503-5p,hsa-miR-299-3p and hsa-miR-191-5p,seven miRNAs with upstream regulation of LncRNAs.these miRNAs can be competitively bound by LncRNAs to prevent the inhibition of translation of target gene expression by miRNAs.In conclusion,our study identified four esophageal adenocarcinoma independent prognostic genes and their upstream regulatory molecules.These genes are involved in the ferroptosis regulation of cells and also play an important role in tumor therapy and drug resistance as one of the disease therapeutic targets.The study suggests that by targeting ATF3,ATM,ATG5,HMGB1 and their upstream regulatory molecules is a new direction for the treatment of esophageal adenocarcinoma.
基金The study was reviewed and approved by the Ethics Committee of the Second Hospital of Hebei Medical University(No.2021-R241).
文摘BACKGROUND Recent studies have emphasized the emerging importance of long noncoding RNAs(lncRNAs)in colorectal cancer(CRC).However,the functions and regulatory mechanisms of numerous lncRNAs in CRC have not been fully elucidated.AIM To explore the functional role and underlying molecular mechanisms of lncRNA TNFRSF10A-AS1 in CRC.METHODS TNFRSF10A-AS1 expression was measured by quantitative real-time polymerase chain reaction in CRC,and the relationship between TNFRSF10A-AS1 levels and the clinicopathological features of CRC patients was analyzed.The effect of TNFRSF10A-AS1 expression on CRC proliferation and metastasis was examined in vitro and in vivo.Mechanistically,we investigated how TNFRSF10A-AS1 is involved in CRC as a competitive endogenous RNA.RESULTS TNFRSF10A-AS1 was expressed at a high level in CRC and the upregulation of TNFRSF10A-AS1 was associated with advanced T grade and tumor size in CRC patients.A functional investigation revealed that TNFRSF10A-AS1 enhanced the proliferation,migration ability and invasion ability of colon cancer cells in vitro and in vivo.A mechanistic analysis demonstrated that TNFRSF10A-AS1 acted as a miR-3121-3p molecular sponge to regulate HuR expression,ultimately promoting colorectal tumorigenesis and progression.CONCLUSION TNFRSF10A-AS1 exerts a tumor-promoting function through the miR-3121-3p/HuR axis in CRC,indicating that it may be a novel target for CRC therapy.
基金This study was supported by the fund project of Science and Technology Department of Qinghai Province(2021-ZJ-730).
文摘We analysed four gene microarray datasets by GEO2R and obtained differential genes expressed in oesophageal cancer.To further elaborate the functions of DGEs,this study performed gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis of DEGs.We constructed protein interaction networks of DGEs through the String database and screened core genes.We used the GEPIA online database with the Kaplan-Meier plotter database to verify the expression of Hub genes in expressed normal versus tumour tissues and the effect of Hub genes on overall and disease-free survival in oesophageal cancer.To further understand the relationship between Hub gene and tumour metastasis,we analysed the difference in Hub gene expression in patients without metastatic oesophageal cancer versus those with metastatic oesophageal cancer with the help of the HCMDB database.The relationship between Hub genes and tumour immune infiltration was analysed by the TIMER database.We obtained a total of 149 DEGs,of which 49 were up-regulated genes and 100 were down-regulated genes.These DGEs were importantly enriched in IL-17 signalling pathway,ECM-receptor interactions,p53 signalling pathway,estrogen signalling pathway,complement and coagulation cascade response.We screened 10 Hub genes,MMP9,CXCL8,COL1A1,TIMP1,POSTN,MMP3,MMP1,COL3A1,SERPINE1,LUM,among 149 DGEs.hub genes were all up-regulated in expression in esophageal cancer tissues,in addition,MMP9,T1MP1,CXCL8,POSTN and The expression of COL3A1,LUM,MMP1,MMP3,MMP9,POSTN,SERPINE1 and TIMP1 was positively correlated with the infiltration of immune cells in the tumor microenvironment.In conclusion,our study identified 10 signature genes for oesophageal cancer.These genes are associated with the development,metastasis,prognosis and immune infiltration of oesophageal cancer and may be markers of development,metastasis and prognosis as well as targets for immunotherapy.
基金supported by the Chinese National Scientific Research Special-Purpose Project in Public Health Profession Funds[No.201002020]National Natural Science Foundation of China[81421003 and 81627807]+1 种基金National Key Research and Development Plan[2017YFC0908300]Independent Funds of the Key Laboratory[CBSKL2015Z01].
文摘背景:单中心或小样本研究数据显示,染色内镜用于溃疡性结肠炎(UC)患者的瘤变监测可能优于白光内镜。我们进行了一项前瞻性随机试验,通过对UC患者的长期随访,比较白光内镜加靶向活检(WLT)、白光内镜加随机活检(WLR)与染色内镜加靶向活检(CET)的肿瘤检出率。方法:前瞻性纳入2012年3月至2013年12月间11个医学中心收治的UC患者,随机分为WLT、WLR、CET三组。三组患者均仅行高清内镜检查,每年内镜随访一次,直至2017年12月。结果:中位随访55个月,122例入组患者完成了447次内镜检查,纳入最终的完成方案分析,其中WLT组43例,WLR组40例,CET组39例。在21例患者的29次肠镜检查中,共发现34个瘤变。WLR组和CET组诊断瘤变的肠镜检查比例高于WLT组(8.1%和9.7%vs 1.9%;P=0.014,P=0.004)。WLR组活检样本数量显著多于WLT组和CET组(16.4±5.1 vs 4.4±1.4和4.3±3.5;均P<0.001)。在后半程随访中(37-69个月),CET组诊断瘤变的肠镜比例显著高于WLT组(13.3%vs 1.6%,P=0.015),较WLR组则显示出了增高的趋势(13.3%vs 4.9%,P=0.107)。结论:对于UC患者的癌变/瘤变长期监测,CET比WLT更加高效,比WLR更加简单,尤其适用于3年以上的长期随访。本研究于www.chictr.org.cn进行注册(ChiCTR1900023689)。
